MicroRNA-based discovery of barriers to dedifferentiation of fibroblasts to pluripotent stem cells

Judson, Robert L.; Greve, T.; Parchem, Ronald J.; Blelloch, Robert

doi:10.1038/nsmb.2665

Cited by 59 publications

(61 citation statements)

References 61 publications

(103 reference statements)

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“…Introduction of exogenous miR-290/302 ESCC miRNAs along with OSK leads to increased reprogramming efficiency (Judson et al, 2009). In this context, it appears miR-290/302 enhances the mesenchymal-to-epithelial transition and leads to an overall reduction in stochastic gene activation that typifies the early phase of reprogramming (Subramanyam et al, 2011; Judson et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Two miRNA Clusters Reveal Alternative Paths in Late-Stage Reprogramming

Parchem

Judson

et al. 2014

Cell Stem Cell

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Summary Ectopic expression of specific factors such as Oct4, Sox2, and Klf4 (OSK) is sufficient to reprogram somatic cells into induced pluripotent stem cells (iPSCs). In this study, we examine the paths taken by cells during the reprogramming process by following the transcriptional activation of two pluripotent miRNA clusters, miR-290 and miR-302, in individual cells in vivo and in vitro using knock-in reporters. During embryonic development and embryonic stem cell differentiation, all cells sequentially expressed miR-290 before miR-302. By contrast, during OSK-induced reprogramming cells activated the miRNA loci in a stochastic, non-ordered manner. However, addition of Sall4 to the OSK cocktail led to a consistent reverse sequence of locus activation (miR-302 then miR-290) and increased reprogramming efficiency. These results demonstrate that cells can follow multiple paths during late stages of reprogramming, and that the trajectory of any individual cell is strongly influenced by the combination of factors introduced.

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Section: Discussionmentioning

confidence: 99%

Two miRNA Clusters Reveal Alternative Paths in Late-Stage Reprogramming

Parchem

Judson

et al. 2014

Cell Stem Cell

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“…Interestingly, miR-181 expression was also detected in lineage markers negative, undifferentiated progenitor cells [22], and in CD34 + cells, where it is involved in the inhibition of differentiation [27]. The miR-181 family also plays a significant role in the enhancement of OCT4, SOX2, and KLF4-driven reprogramming and promotion of pluripotency [28], consistent with its engagement in stem cell renewal and maintenance. These findings are consistent with our observations made using IM-resistant CML cells that were generated by prolonged exposure to IM.…”

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confidence: 83%

Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

Chorzalska

Kim

Roder

et al. 2017

Stem Cells and Development

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Despite the success of tyrosine kinase inhibitor (TKI) therapy in chronic myelogenous leukemia (CML), leukemic stem/progenitor cells remain detectable even in the state of deep molecular remission. Mechanisms that allow them to persist despite continued kinase inhibition remain unclear. We have previously shown that prolonged exposure to imatinib mesylate (IM) results in dysregulation of Akt/Erk 1/2 signaling, upregulation of miR-181a, enhanced adhesiveness, and resistance to high IM. To characterize the molecular basis and reversibility of those effects, we applied gene and protein expression analysis, quantitative phosphoproteomics, and direct miR-181a inhibition to our cellular model of CML cells subjected to prolonged exposure to IM. Those cells demonstrated upregulation of pluripotency markers (SOX2, SALL4) and adhesion receptors (CD44, VLA-4, CXCR4), as well as downregulation of Hippo signaling and upregulation of transcription coactivator YAP. Furthermore, inhibition of miR-181a using a microRNA sponge inhibitor resulted in decreased transcription of SOX2 and SALL4, decreased activation of YAP, and increased sensitivity to IM. Our findings indicate that long-term exposure to IM results in dysregulation of stem cell renewal-regulatory Hippo/YAP signaling, acquisition of expression of stem cell markers and that experimental interference with YAP activity may help to restore chemosensitivity to TKI.

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“…Indeed, certain miRNAs have been shown to have an impact on mRNAs that participate in a common cellular pathway (for example, see Judson et al 23 ). Conversely, a single mRNA might be jointly regulated by more than one miRNA (Figure 1b), as in the example of p21/Waf, which is targeted by many miRNAs.…”

Section: Mirnas and Their Targetsmentioning

confidence: 99%

The complexity of miRNA-mediated repression

2014

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Since their discovery 20 years ago, miRNAs have attracted much attention from all areas of biology. These short (B22 nt) non-coding RNA molecules are highly conserved in evolution and are present in nearly all eukaryotes. They have critical roles in virtually every cellular process, particularly determination of cell fate in development and regulation of the cell cycle. Although it has long been known that miRNAs bind to mRNAs to trigger translational repression and degradation, there had been much debate regarding their precise mode of action. It is now believed that translational control is the primary event, only later followed by mRNA destabilisation. This review will discuss the most recent advances in our understanding of the molecular underpinnings of miRNA-mediated repression. Moreover, we highlight the multitude of regulatory mechanisms that modulate miRNA function.

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MicroRNA-based discovery of barriers to dedifferentiation of fibroblasts to pluripotent stem cells

Cited by 59 publications

References 61 publications

Two miRNA Clusters Reveal Alternative Paths in Late-Stage Reprogramming

Two miRNA Clusters Reveal Alternative Paths in Late-Stage Reprogramming

Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

The complexity of miRNA-mediated repression

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